Severe Transfusion Reactions and their ED-focused management

Authors: Richard Wroblewski, MD (EM Resident Physician, Temple EM) and Zachary Repanshek, MD (Assistant Professor of EM / APD, Temple EM) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

The decision to transfuse blood is made based on the clinical combination of hemoglobin level, concurrent comorbidities, and the overall clinical picture.  Once the decision is made, granted that our patient is stable and competent, it is our job to inform and consent the patient to receive blood.  As a clinician, we run through the list of possibilities that can occur when receiving blood: fevers, allergic reactions, infections, lung injury, and possibly death.  We explain that we try to minimize risks in every way possible; however, we must make the patient aware so that they understand the risks.  But how rare are these adverse events, and how do we manage them?

In 2011 approximately 20,933,000 units of blood product were transfused. The average patient received 2.6 units per transfusion¹. Based on these numbers, almost 8,000,000 people in America received a blood transfusion in 2011.  In that year, there were 51,000 reportable reactions, and only 317 of them required increased levels of critical management: ICU care, intubation, or pressor support¹.

The graph demonstrates the likelihood of transfusion reaction as reported in The National Blood Collection and Utilization Survey Report¹. One should note the pie chart represents <1% of all blood transfusions during the data year¹.   Although these reactions are rare and the fact that a majority of reactions are benign in nature, it is important to recognize the acute, emergent transfusion reactions. For the purpose of consent, the prevalence of viral infections should be noted. Current screening techniques have reduced the risk of viral transmission lower than any other adverse event: HIV is 1: 1,467,000 units / Hepatitis C is 1: 1,149,000 units / and Hepatitis B is 1: 357,000 units².

Acute Hemolytic Reactions

Acute hemolytic reaction is the most severe reaction, and in most cases, the easiest to prevent. This reaction occurs most commonly with ABO incompatibility due to human or systematic error³. The reaction often occurs within minutes of initiation, and this can help delineate this reaction from febrile-non-hemolytic reaction which typically occurs greater than 1 hour post transfusion⁴.

The patient will present with chills, agitation, fever, tachycardia, hypotension, abdominal and back pain, nausea, and progress to have changes in urine color, jaundice, and possibly diffuse bleeding due to coagulopathy. The symptoms often occur within minutes of transfusion initiation due to high levels of hemolysis within the body, resulting in spilling of free hemoglobin and diffuse proliferation of inflammatory cytokines⁵.

Treatment for all transfusion reactions begins with stopping the transfusion and calling the blood bank for further guidance and monitoring. In a serious transfusion reaction, you will want to send a set of new labs immediately to trend: type and cross, DAT (direct antiglobulin test), CBC, CMP, haptoglobin, fibrinogen levels, LDH, PT, and PTT⁶. These labs and their trends will help guide further treatment.

In the case of acute hemolytic reaction, fluid resuscitation should be initiated early to promote renal perfusion. The goal is to prevent kidney injury secondary to hypoperfusion and occlusive thrombi from DIC⁵. Therapy should be as follows:

• IV fluids with goal urine output of 1cc/kg/hr⁶.
  • Furosemide 40-80mg IV can be used to augment urine output if the patient is oliguric; however, it should be stopped if there is no response or persistent hypotension within 4 hours of therapy⁶.
  • Continued hypotension after IV fluids should be treated with dopamine (2-5micrograms/kg/min⁶. Other vasopressors such as epinephrine and norepinephrine should be used with caution due to decreased renal perfusion.
  • If DIC is suspected, the use of replacement therapy should be used as follows:
  • FFP used if PT greater than 1.5
  • Cryoprecipitate if fibrinogen levels below 1g/L
  • Platelets replaced if count is below 50,000/uL⁶
  • Dialysis can be used to remove the immune complexes⁵.
  • Red Blood Cell Exchange Transfusion has been successful in a few case reports⁷.

Febrile Reaction

Febrile non-hemolytic transfusion reaction (FNHTR) is the most common transfusion reaction, occurring during the transfusion to 8 hours after.  Patients may also present will chills. It is due to recipient antibodies against donor leukocytes most commonly. With its similarity to acute hemolytic reaction, any fever warrants immediate discontinuation of the transfusion.  However, FNHTR is benign, with no sequelae. Acetaminophen should be provided^1,3-5.

Transfusion Related Acute Lung Injury 

Transfusion Related Acute Lung Injury is currently the most common cause of transfusion related fatalities⁸. According to current consensus, TRALI is defined as new lung injury within 6 hours of transfusion: hypoxemia <90% and CXR with infiltrates and lack of other risk factors⁹.

TRALI occurs within the first 6 hours of transfusion and presents with dyspnea, tachypnea, and hypoxemia. Patients often are noted to have associated rigors, tachycardia, fever, and hypotension¹⁰. Diagnostically, a chest X-ray will be the most beneficial; however, the findings can range from a small amount of bilateral infiltrate to an entire white-out of the lungs as seen in ARDS¹¹. Laboratory testing is not specific but can be helpful; often a leukopenia and thrombocytopenia can be seen as the lungs sequester these inflammatory cells, but these are not diagnostic for TRALI^10,11.

The current theory on the pathogenesis of TRALI is based on the two-hit model. The first hit is an underlying patient factor that causes adherence of primed neutrophils in the pulmonary endothelium^11,12.  At risk patients include those with sepsis, on mechanical ventilation, acute renal failure, liver disease, chronic alcoholics, patients in shock, smokers, and those with a history of blood cancer¹³. The second hit occurs when the blood transfusion itself causes activation of the primed neutrophils within the lungs resulting in inflammatory changes that cause acute pulmonary edema mostly due to increased capillary permeability^11,12.

In general, TRALI has a favorable prognosis with mortality ranging between 5-10%¹⁴. Despite its prognosis, a significant number of patients (70-90%) require mechanical ventilation¹¹.

First line treatment is to stop the transfusion and call the blood bank. Initially high flow oxygen should be administered to improve oxygenation; however, as the pulmonary edema continues, the need for mechanical ventilation becomes more likely. Due to its clinical similarity to ARDS, patients with TRALI are suggested to have restrictive tidal volume ventilation¹¹. There has been little evidence for the use of corticosteroids and diuretics in these patients¹¹.

Allergic Reactions

Allergic reactions occur in 1-3% of transfusions and can range from rash to anaphalyxis¹⁵. Although common, there is little evidence to show any benefit to pre-treating all patients with antihistamines, and at this time, it is not recommended¹⁶.  Patients typically develop symptoms within minutes and present with common signs of an allergic response: rash, urticaria, and itching. These symptoms can quickly progress to anaphylactic reactions with hypotension, angioedema, and respiratory distress. 

All reactions should prompt the emergency physician to stop the transfusion immediately and provide antihistamines. If only a mild reaction occurs and antihistamines provide relief, the transfusion can continue.  If symptoms appear to be more severe, epinephrine should be administered immediately. Monitoring for signs of hypotension and airway compromise may prompt further interventions⁶.

Transfusion Associated Circulatory Overload

Transfusion Associated Circulatory Overload can be thought of as pulmonary edema from acute heart failure secondary to blood transfusion. The reaction is associated with a significant increase in morbidity and mortality as well as length of hospital stay¹⁹.  TACO is more likely to occur in patients with a history of congestive heart failure, renal failure, hemorrhagic shock, and those receiving multiple units of blood product¹⁹. Patients typically present within 6 hours of transfusion with signs of acute pulmonary edema and heart failure: new respiratory distress, hypertension, new pulmonary edema, widened pulse pressure, and increased JVD. 

Diagnostically, TACO is very difficult to differentiate from TRALI, and the chest radiograph is similar to that seen in TRALI. The use of BNP to measure heart strain in the setting of TACO has been studied with conflicting results and may only be useful if a pre-transfusion BNP is collected^21,22.

Physiologically, TACO can be thought of as volume overload due to blood transfusion. Therefore, the problem is simply a volume overload and should be treated as such.

Treatment for TACO can start before the transfusion even begins. When high risk patients are identified, preventative measures should be put in place to avoid circulatory overload:

• Slower transfusion rates (<120cc/hr), 1 unit at a time with reassessment in between multiunit transfusions, and intravenous dose of furosemide (40mg) prior to transfusion²⁰.

If TACO does occur, treatment starts with stopping the transfusion and promoting oxygenation and clearance by sitting the patient upright, providing supplemental oxygen, and providing nitrates/diuretics to remove excess volume and reduce preload. In cases of significant respiratory distress, non-invasive positive pressure ventilation can be beneficial. If these methods fail, therapeutic phlebotomy can be used ⁶.

Sepsis

Introduction of bacteria to the patient during transfusion occurs with a quoted incidence between 1:38,000 for packed red blood cells and 1:2000 for platelets; however, adverse reactions from bacterial contamination remain low at 1:250,000 and 1:25,000, respectively²³. Most commonly, packed red blood cells are contaminated with organisms such as Yersinia Entercolitica, Serratia, and Psuedomonas, whereas platelet transfusions are more likely to grow skin contaminants such as Staphylococcus aureus and Streptococci²⁴.

Patients will rapidly develop high fevers, chills, rigors, tachycardia, and hypotension along with dyspnea and can progress into DIC⁶. These symptoms are very similar to acute hemolytic transfusion reaction and therefore must often be considered together and treated similarly. If sepsis is considered, along with testing for AHTR, blood cultures from the unit of blood being transfused and a separate culture from the patient should be sent to the lab and broad spectrum antibiotic initiated based upon most likely culprits.  These patients should have their transfusions stopped immediately, and begin fluid resuscitation along with antibiotic treatment before any results return.

Pearls and Pitfalls: Approach to Reactions

• Maintaining high clinical suspicion for reaction will save lives; although rare these are serious reactions.
• Report any reaction to the blood bank to allow for reporting and monitoring.
• For any reaction: stop transfusion, call blood bank, and double check that the correct patient received the correct blood.
• Most reactions with fever will require a full laboratory work-up for signs of hemolysis and infection: CMP, CBC, Haptoglobin, DAT, LDH, PT, PTT, fibrinogen, blood culture, and gram stains from patient and sample, and a type and cross.
• Any signs of dyspnea require a chest radiograph; if there is a fever and hypotension, it is more likely to be TRALI than TACO.
• Treatment for all is largely supportive; however, in severe reactions antibiotics can be initiated for any suspicion of septic transfusion.

This post is sponsored by www.ERdocFinder.com, a supporter of FOAM and medical education, who with their sponsorship are making FOAM material more accessible to ER physicians around the world.

References/Further Reading:

1) United States Department of Health and Human Services.  The 2011 National Blood Collection and Utilization Survey Report.  2013. Accessed Feb 5,2017. http://www.hhs.gov/ash/bloodsafety/2011-nbcus.pdf.

2) Epstein, J. S. and Holmberg, J. A. (2010), Progress in monitoring blood safety. Transfusion, 50: 1408–1412. doi:10.1111/j.1537-2995.2010.02728.x

3) Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2005. Chapter 3, Blood transfusions and the immune system. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2265/

4) Chaffin, J. (2012 November/December) Transfusion Reactions [Audio Podcast] Retrieved from http://www.bbguy.org/pdf/2012_11_TX_RXNs.pdf

5) Strobel, E. (2008). Hemolytic Transfusion Reactions. Transfusion Medicine and Hemotherapy, 35(5), 346–353. http://doi.org/10.1159/000154811

6) Adewoyin, A., & Oyewale, O. (2015). Complications of Allogeneic Blood Transfusion: Current Approach to Diagnosis and Management. International Blood Research & Reviews, 3(4), 135-151. doi:10.9734/ibrr/2015/17874

7) Rose, S. S., George, S., Wong, S., Tenorino, G., & Kuriyan, M. (2007). Red Blood Cell Exchange Transfusion (RBCET) in the Management of Acute Hemolytic Transfusion Reaction (AHTR).. Blood, 110(11), 4021. Accessed February 05, 2017. Retrieved from http://www.bloodjournal.org/content/110/11/4021.

8) L Holness, MA Knippen, L Simmons, PA Lachenbruch. Fatalities caused by TRALI. Transfus Med Rev, 18 (2004), pp. 184–188

9) Goldman, M., Webert, K. E., Arnold, D. M., Freedman, J., Hannon, J., & Blajchman, M. A. (2005). Proceedings of a Consensus Conference: Towards an Understanding of TRALI. Transfusion Medicine Reviews, 19(1), 2-31. doi:10.1016/j.tmrv.2004.10.001

10) EA Fadeyi, MM De Los Angeles, AS Wayne, HG Klein, SF Leitman, DF Stroncek. The transfusion of neutrophil-specific antibodies causes leukopenia and a broad spectrum of pulmonary reactions. Transfusion. 2007 Mar;47(3):545-50.

11)Vlaar, A. P., & Juffermans, N. P. (2013). Transfusion-related acute lung injury: a clinical review. The Lancet, 382(9896), 984-994. doi:10.1016/s0140-6736(12)62197-7

12) CC Silliman The two-event model of transfusion-related acute lung injury Crit Care Med, 34 (2006), pp. S124–S131

13) Toy, P., Gajic, O., Bacchetti, P., Looney, M. R., Gropper, M. A., Hubmayr, R., . . . Matthay, M. A. (2011). Transfusion-related acute lung injury: incidence and risk factors. Blood, 119(7), 1757-1767. doi:10.1182/blood-2011-08-370932

14) SB Moore. Transfusion-related acute lung injury (TRALI): clinical presentation, treatment, and prognosis Crit Care Med, 34 (2006), pp. S114–S117

15) Hendrickson, J. E., & Hillyer, C. D. (2009). Noninfectious Serious Hazards of Transfusion. Anesthesia & Analgesia, 108(3), 759-769. doi:10.1213/ane.0b013e3181930a6e

16) Geiger, T. L., & Howard, S. C. (2007). Acetaminophen and Diphenhydramine Premedication for Allergic and Febrile Non-hemolytic Transfusion Reactions: Good Prophylaxis or Bad Practice? Transfusion Medicine Reviews, 21(1), 1–12. http://doi.org/10.1016/j.tmrv.2006.09.001

17) Haji, A. G., Sharma, S., Vijaykumar, D. K., & Paul, J. (2008). Transfusion related acute lung injury presenting with acute dyspnea: a case report. Journal of Medical Case Reports,2(1). doi:10.1186/1752-1947-2-336

18) Silvergleid, A.J. (2016) Approach to the patient with a suspected acute transfusion reaction. In Kleinman, S. (Ed), Uptodate.

19) Murphy, E. L., Kwaan, N., Looney, M. R., Gajic, O., Hubmayr, R. D., Gropper, M. A., … the TRALI Study Group. (2013). Risk Factors and Outcomes in Transfusion-associated Circulatory Overload. The American Journal of Medicine, 126(4), 357.e29–357.e38. http://doi.org/10.1016/j.amjmed.2012.08.019

20) Alam, A. A. (04/2013). Transfusion medicine reviews: The prevention of transfusion-associated circulatory overload. Elsevier. doi:10.1016/j.tmrv.2013.02.001

21) Li, G., Daniels, C. E., Kojicic, M., Krpata, T., Wilson, G. A., Winters, J. L., … Gajic, O. (2009). The Accuracy of Natriuretic Peptides (BNP and NT-pro-BNP) in the Differentiation between Transfusion Related Acute Lung Injury (TRALI) and Transfusion Related Circulatory Overload (TACO) in the Critically Ill. Transfusion, 49(1), 13–20. http://doi.org/10.1111/j.1537-2995.2008.01941.x

22) Zhou, L. L. (07/2005). Transfusion (philadelphia, pa.): Use of B-natriuretic peptide as a diagnostic marker in the differential diagnosis of transfusion-associated circulatory overload. Blackwell Publishing. doi:10.1111/j.1537-2995.2005.04326.x

23) Hillyer CD, Josephson CD, Blajchman MA, et al. Bacterial contamination of blood products: risks, strategies, and regulation. Hematology 2003: American Society of Hematology Educational Program Book. Washington, DC: American Society of Hematology; 2003: 575-589

24) Squires, J. E. J. (11/2011). Southern medical journal (birmingham, ala.): Risks of transfusion. Hop Wechsler. doi:10.1097/SMJ.0b013e31823213b6